The blood coagulation factor XII (hereinafter abbreviated as FXII), which is called a Hageman factor, is a factor which is activated for the first time in the chain reaction of an intrinsic blood clotting. An activated blood coagulation factor XII (the blood coagulation factor XII in an active form, hereinafter abbreviated as FXIIa) activates the blood coagulation factor (FXI). Then, a series of reactions in the reaction system of intrinsic blood clotting as shown in FIG. 1 proceeds. Finally, an insoluble fibrin is produced whereupon the intrinsic blood clotting reaction is accomplished.
A series of the mechanisms or reactions for dissolving the fibrin clot is a fibrinolysis system. FXIIa participates in the initial phase of the fibrinolysis system. Thus, as shown in FIG. 2, plasmin plays a main role in the fibrinolysis. Plasmin is present in plasma as an insoluble plasminogen. However, FXIIa is one of the activators which activate plasminogen to obtain plasmin. The reaction by which the fibrin clot produced as such by coagulation of plasmin is degraded is the final stage of the fibrinolysis system.
In addition, activation of FXII is an initial stage of the plasma kallikrein-kinin system. In the plasma kallikrein-kinin system, it is believed that a series of enzymatic reaction systems takes place as a result of the activation of FXII by injury, invaded stimulation, etc. to the tissues in vivo. Thus, as shown in FIG. 3, the activated FXIIa acts on the plasma prekallikrein which is also present in the plasma, and converts it to a plasma kallikrein which is an enzyme in an active form. Then, the plasma kallikrein acts on the high-molecular-weight kininogen (hereinafter abbreviated as an HK) to liberate bradykinin.
Kinins, such as bradykinin, which are the products in the kallikrein-kinin system exhibit various physiological actions. Examples of the physiological actions are a decrease in blood pressure due to dilation of peripheral blood vessels, promotion of permeability of blood vessels, contraction or relaxation of smooth muscle, induction of pain, induction of inflammation, migration of leucocytes, liberation of catecholamine from the adrenal cortex, etc. Kinins are also known as mediators in acute inflammation including allergic reactions whereby their existence in vivo has a profound significance.
As such, FXIIa is a very important factor in the initial stage of the intrinsic blood clotting system, fibrinolysis system, and plasma kallikrein-kinin system. Accordingly, substances which affect the production of FXIIa may be useful pharmaceuticals or drugs in the areas of blood clotting and fibrinolysis. In addition, substances which affect the production of FXIIa may be useful as antiinflammatory, analgesic, and antiallergic drugs because bradykinin liberated in the plasma kallikrein-kinin system has various physiological activities as mentioned above.
The present invention provides a method for determining the action and activity of a substance which inhibits or promotes the production of FXIIa which is an initiation factor of the intrinsic blood clotting system, fibrinolysis system and plasma kallikrein-kinin system in a simple, convenient, prompt and precise manner. The method is a very effective means for ascertaining the action helpful in adjusting the bioregulations as mentioned above and also for developing such drugs.